Post-SCI effects of BDNF and epidural stimulation on inhibitory RORb interneurons

SCI 后 BDNF 和硬膜外刺激对抑制性 RORb 中间神经元的影响

• 批准号: 10536779
• 负责人: Nicholas Stachowski
• 金额: $ 4.68万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536779
• 关键词: Acute; Address; Adult; Affect; Behavior; Brain-Derived Neurotrophic Factor; Bypass; Cells; Chest; Chronic; Combined Modality Therapy; Electrophysiology (science); Fiber; Foundations; Future; Genetic; Goals; Hindlimb; Hyperreflexia; In Vitro; Individual; Injury; Interneurons; Intervention; Lesion; Locomotor Recovery; Measures; Mediating; Methods; Motor; Mus; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Nuclear Orphan Receptor; Orphan; Outcome; Paralysed; Pathway interactions; Physiological; Population; Protocols documentation; Recovery of Function; Rehabilitation therapy; Retinoids; Rodent; Role; Sensorimotor functions; Sensory Thresholds; Signal Transduction; Source; Spasm; Spinal; Spinal Cord; Spinal Injections; Spinal cord injury; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; Viral; Weight; Work; central pattern generator; cohort; combinatorial; designer receptors exclusively activated by designer drugs; disability; dorsal horn; experimental study; functional outcomes; improved; insight; loss of function; motor recovery; mouse model; nervous system disorder; neurotransmission; neurotrophic factor; novel; novel therapeutic intervention; overexpression; pain reduction; patch clamp; presynaptic; prevent; receptor; recruit; rehabilitation strategy; relating to nervous system; sensory gating; sensory mechanism; side effect; spasticity; spinal nerve posterior root; therapeutic target; treatment effect

ABSTRACT The number of individuals living with a spinal cord injury (SCI) continues to rise but rehabilitative strategies for functional locomotor recovery remain inadequate. Spinal circuits remain intact and functional even in the absence of descending control and serve as therapeutic targets. Neurotrophic factors have been shown to enhance neuronal plasticity and experimental viral overexpression of brain-derived neurotrophic factor (AAV- BDNF) is sufficient activate locomotor circuits to elicit alternating plantar stepping of hindlimbs after complete SCI in rodents. However, viral BDNF effects also induce a hyperreflexive state and hindlimb spasms. Sub-motor threshold epidural stimulation (ES) can reduce hyperreflexia in individuals living with SCI but the mechanism of action underlying this effect remains elusive. We have recently combined viral BDNF treatment with daily ES in a mouse model of complete SCI to identify synergistic effects between these two potentially complementary therapeutic strategies and our preliminary findings suggest a possible role for ES in mitigating BDNF-induced hyperreflexia while maintaining locomotor improvements. In addition to chronic disability, a large number of individuals living with SCI also suffer from hyperreflexia and our approach allows for exploration of treatment and mechanism in parallel. Spinal interneurons are the primary source of inhibitory control below the level of injury, and we will use precise physiological and genetic methods to identify the neural components subject to plasticity after SCI and subsequent intervention with viral BDNF, with or without ES. In this proposal, we focus on a population of inhibitory interneurons (INs) expressing the retinoid orphan nuclear receptor (RORb) which has recently been shown to gate low threshold sensory afferent signals via primary afferent depolarization (PAD), a spinal mechanism of presynaptic inhibition. RORb INs are likely to be affected by our combinatorial approach as they express TrkB receptors, the cognate receptor for BDNF, and are recruited upon activation of proprioceptive fibers, potential effector neurons of low intensity ES. Our central hypotheses are that: 1) BDNF increases the cellular excitability of RORb INs and enhances PAD pathway activity but this is insufficient to counteract other actions of BDNF leading to hyperreflexia, 2) the RORb-mediated PAD pathway is acutely enhanced during concurrent ES to limit BDNF-induced hyperreflexia and promote improvements in hindlimb stepping after complete SCI. We will investigate changes in the excitability of RORb INs at the presynaptic inhibitory circuit, together with behavior to determine the effects of SCI and treatment with BDNF alone and in combination with ES. This proposal will provide mechanistic insight into SCI-induced plasticity and identify therapeutic interactions that are associated with functional motor recovery as well as those underlying loss of function, both of which will benefit rehabilitative efforts to address intractable neurological disorders that extend beyond locomotor disability.

抽象的 患有脊髓损伤（SCI）的人数继续增加，但康复策略 功能运动恢复仍然不足。脊柱电路即使在 缺乏降降控制并充当治疗靶标。神经营养因素已显示为 增强脑衍生神经营养因子的神经元可塑性和实验性病毒过表达（AAV- bdnf）足够激活运动电路，可以在完成后引起后肢的足底垫脚 啮齿动物的SCI。然而，病毒BDNF效应也会引起过度反射状态和后肢痉挛。亚运动 阈值硬膜外刺激（ES）可以减少患有SCI的个体的过度反射症，但机制的机制 这种效果的作用仍然难以捉摸。我们最近将病毒BDNF治疗与每日ES合并 完整SCI的小鼠模型，以识别这两个潜在互补之间的协同作用 治疗策略和我们的初步发现表明，ES在减轻BDNF诱导的 在维持运动改善的同时，过度反射。除了慢性残疾，大量 患有SCI的人也患有超反射症，我们的方法可以探索治疗和 并行机构。脊柱中间神经元是抑制性控制的主要来源，低于损伤水平， 我们将使用精确的生理和遗传学方法来识别受可塑性的神经成分 在SCI和随后干预病毒BDNF之后，有或没有ES。在此提案中，我们专注于 表达类维生素类孤儿核受体（RORB）的抑制性中间神经元（INS）的种群 最近显示，通过初级传入去极化（PAD）A gate低阈值感官传入信号 突触前抑制的脊柱机制。 Rorb ins可能会受到我们组合方法的影响 它们表达TRKB受体，BDNF的同源受体，并在激活后招募 低强度ES的纤维，潜在效应神经元。我们的中心假设是：1）BDNF增加 RORB INS和增强PAD途径活动的细胞兴奋性，但这不足以抵消其他 BDNF导致超反射症的作用，2）RORB介导的PAD途径在期间明显增强 并发ES限制BDNF诱导的过度反射症，并促进后肢的改善 完整的科幻。我们将研究RORB INS在突触前抑制回路上的兴奋性变化， 与行为一起确定SCI和单独使用BDNF治疗的影响，并结合使用 es。该建议将提供有关SCI诱导的可塑性的机械洞察力，并确定治疗相互作用 与功能性运动恢复以及功能的潜在损失相关的，这两者都将 利益康复的努力，以解决超越运动障碍的顽固性神经系统疾病。